An aerosol is a gaseous suspension of fine solid or liquid particles. An aerosol formulation, in turn, is one which comprises a solution or suspension of an active ingredient in a liquid which consists of a propellant and an any necessary solvent or surfactant. The propellant will generally be a low boiling liquid, which volatilizes under ambient conditions of temperature and pressure. The formulation is held, under pressure, in a container, and released from the container through a valve, to form an aerosol spray.
A great many substances are designed to be delivered in the form of aerosol sprays, such as, for example, medicaments, insecticides and paints. While the present invention is applicable to the preparation of aerosol formulations in general, it is especially applicable to the preparation of aerosol formulations of medicaments which are intended to be administered, by inhalation, in the form of metered doses of aerosol spray, using a dispensing device called a metered dose inhaler (MDI).
To deliver an aerosol spray of uniform composition, an aerosol formulation should be as homogeneous as possible. For an aerosol formulation which comprises a solid as its active ingredient, the active ingredient should be finely divided and it, together with the propellant and other formulation components, such as solvent or surfactant, should form a uniformly dispersed suspension. Thus, it is generally necessary to subject an aerosol formulation to some sort of homogenization procedure prior to packaging.
As aerosol formulations contain propellants which become gaseous at normal temperature and pressure (about 20.degree. C. and 1 atmosphere), the homogenization of an aerosol formulation can be problematical. In order to avoid volatilization, an aerosol propellant must be handled at either elevated pressure or at a temperature which is below its boiling point.
An homogenization apparatus, of the sort typically used for the homogenization of an aerosol formulation in accordance with current practice, comprises a containment vessel and a propeller-like rotor which impels liquid contained in the vessel against a stator, causing the liquid to be homogenized. Currently available homogenizers of this design (rotor/stator homogenizers) are not adapted to operate with the contents of the containment vessel under substantially elevated pressure. That is to say, a homogenization apparatus of the rotor/stator design can operate only at ambient pressure or at slightly elevated pressure; it cannot operate at an elevated pressure which would be sufficient to keep a volatile material in its liquid state. Thus, a rotor/stator homogenizer can only be used to homogenize a mixture which contains a low-boiling, volatile propellant if the process is carried out at a temperature below the boiling point of the propellant. Where this is not desired or possible, as in cases wherein the constituents of the aerosol formulation are not sufficiently miscible at reduced temperature, another expedient can be resorted to. In such situations, a non-volatile product concentrate, consisting of the active ingredient and a relatively high boiling, relatively non-volatile liquid is first produced. As the product concentrate is relatively non-volatile, it can be homogenized using a rotor/stator homogenizer at ambient temperature and pressure. Once homogenized, the product concentrate can be admixed with the propellant, under pressure, to form an homogenous aerosol formulation.
Thus, for example, it is known in the pharmaceutical art that an inhalation aerosol formulation of a medicament, containing a relatively low boiling chloroflurocarbon (CFC) as propellant, such as, for example CFC 12 (CCl.sub.2 F.sub.2, T.sub.b /.degree. C.=-29.8) or CFC 114 (C.sub.2 Cl.sub.2 F.sub.4, T.sub.b /.degree. C.=3.8), can be made by first first preparing a product concentrate which comprises the active medicament as a finely divided solid, a relatively high boiling CFC, such as for example CFC 11 (CCl.sub.3 F, T.sub.b /.degree. C.=23.75) and a surfactant or suspending agent (e.g. soy lecithin, oleic acid, Span.RTM., etc.). This product concentrate can be homogenized at ambient temperature and pressure, using a rotor/stator homogenizer. Once homogenized, the product concentrate and the relatively low boiling CFC propellant are introduced into a pressure vessel, where they are mixed to form a completed and homogenous formulation. The completed formulation is then filled into dispensing devices, such as MDI's, working either under elevated pressure and ambient temperature (by back-filling through the valves of capped containers), or at reduced temperature and ambient pressure (wherein the containers are filled and then capped).
In the aforementioned formulation, the relatively high boiling CFC serves three important and distinct functions. First, it serves as a solvent for the suspending agent, such as soy lecithin. To ensure accurate, reproducible dosing, it is necessary for the suspending agent to be completely soluble in the product concentrate (in which the high boiling CFC is the only CFC present) and in the entire formulation (in which both high and low boiling CFCs are present). Second, with regard to its interaction with the solid drug particles, the high boiling CFC serves as a dispersion medium. Third, it contributes to the overall vapor pressure of the final formulation. The pressure of the formulation is one of the variables that affects the optimization of active ingredient deposition in the lungs of a patient and, therefore, the efficacy of the formulation. In this context, the relatively high boiling CFC is referred to as a propellant, because the final vapor pressure of the formulation is the result of the partial pressure contributions of all of the CFCs used in the formulation.
Recent environmental concerns regarding the use of CFC propellants have led to the substitution of hydrofluorocarbon alkane (HFA) propellants in place of traditional CFCs. It has been found that the above-described methods for preparing aerosol formulations, in which homogenization is accomplished using a rotor/stator homogenizer, at ambient temperature and pressure, cannot generally be used to make HFA-based formulations.
In particular, there are no acceptable high boiling HFAs which can be used to create a non-volatile product concentrate, as is done in the case of the above-described CFC formulation, in which CFC 11 is used. Accordingly, a homogenous mixture of a low boiling HFA, the active drug, a surfactant, and other formulation constituents must be made. It will be readily apparent that the homogenization of a formulation comprising a low boiling HFA must either be carried out at elevated pressure or reduced temperature because the low boiling HFA would otherwise evaporate. However, it is not always possible to carry out the homogenization at reduced temperature since many of the surfactants which are compatible with HFAs are not soluble in the HFA formulation at reduced temperature. Therefore, the homogenization must be carried out at elevated pressure.
Unfortunately, as mentioned before, rotor/stator homogenizers do not presently exist which are adapted to operate under sufficient pressure to prevent the volatilization of a low boiling constituent, such as a propellant. Accordingly, existing techniques cannot be used to homogenize a formulation containing a low boiling constituent, such as an HFA propellant, at ambient temperatures.
As further background, it should be understood that where solid particles of active substance are to be suspended in an aerosol formulation such particles must have a very small and substantially uniform particle size. That is to say, the particles of active ingredient, in order to form an homogenous suspension, must be micronized. Such micronization is usually accomplished by a milling operation which is carried out before the active substance is incorporated into the formulation. Such milling operations are undesirable in that they tend to produce an airborne dust of active substance which represents a costly loss of active material, and which contaminants the production environment, making housekeeping more difficult and creating a possible hazard for workers. Although desirable, the prior art does not provide a method or apparatus whereby a solid active substance can be micronized after it has been incorporated into an aerosol formulation, for example during the homogenization step, so that prior milling can be avoided.